Alkylaminoalkyl-terminated sulfide/sulfonyl-containing propargyl amino-diol compounds for treatment of hypertension

ABSTRACT

Compounds characterized generally as alkylaminoalkyl-terminated sulfide/sulfonyl-containing propargyl amino-diol derivatives are useful as renin inhibitors for the treatment of hypertension. Compounds of particular interest are those of Formula II:  
                 
 
     wherein q is two or three; wherein r is zero or two; wherein R 2  is selected from hydrido, methyl, ethyl and phenyl; wherein R 3  is selected from hydrido, cyclohexylmethyl, benzyl, fluorobenzyl, chlorobenzyl, fluoronaphthylmethyl and chloronaphthylmethyl; wherein R 5  is propargyl or a propargyl containing moiety; wherein R 7  is cyclohexylmethyl; wherein R 8  is selected from n-propyl, isobutyl, cyclopropyl, cyclopropylmethyl, allyl and vinyl; and wherein each of R 12  and R 13  is a group independently selected from methyl, ethyl and isopropyl; or a pharmaceutically-acceptable salt thereof.

FIELD OF THE INVENTION

[0001] Renin-inhibiting compounds are known for control of hypertension.Of particular interest herein are compounds useful as renin inhibitingagents.

BACKGROUND OF THE INVENTION

[0002] Renin is a proteolytic enzyme produced and secreted into thebloodstream by the juxtaglomerular cells of the kidney. In thebloodstream, renin cleaves a peptide bond in the serum proteinangiotensinogen to produce a decapeptide known as angiotensin I. Asecond enzyme known as angiotensin converting enzyme, cleavesangiotensin I to produce the octapeptide known as angiotensin II.Angiotensin II is a potent pressor agent responsible forvasoconstriction and elevation of cardiovascular pressure. Attempts havebeen made to control hypertension by blocking the action of renin or byblocking the formation of angiotensin II in the body with inhibitors ofangiotensin I converting enzyme.

[0003] Classes of compounds published as inhibitors of the action ofrenin on angiotensinogen include renin antibodies, pepstatin and itsanalogs, phospholipids, angiotensinogen analogs, pro-renin relatedanalogs and peptide aldehydes.

[0004] A peptide isolated from actinomyces has been reported as aninhibitor of aspartyl proteases such as pepsin, cathepsin D and renin[Umezawa et al, in J. Antibiot. (Tokyo), 23, 259-262 (1970)]. Thispeptide, known as pepstatin, was found to reduce blood pressure in vivoafter the injection of hog renin into nephrectomized rats [Gross et al,Science, 175, 656 (1971)]. Pepstatin has the disadvantages of lowsolubility and of inhibiting acid proteases in addition to renin.Modified pepstatins have been synthesized in an attempt to increase thespecificity for human renin over other physiologically importantenzymes. While some degree of specificity has been achieved, thisapproach has led to rather high molecular weight hepta- and octapeptides[Boger et al, Nature, 303, 81 (1983)]. High molecular weight peptidesare generally considered undesirable as drugs because gastrointestinalabsorption is impaired and plasma stability is compromised.

[0005] Short peptide aldehydes have been reported as renin inhibitors[Kokubu et al, Biochim. Biophys. Res. Commun., 118, 929 (1984); Castroet al, FEBS Lett., 167, 273 (1984)]. Such compounds have a reactiveC-terminal aldehyde group and would likely be unstable in vivo.

[0006] Other peptidyl compounds have been described as renin inhibitors.EP Appl. #128,762, published 18 Dec. 1984, describes dipeptide andtripeptide glyco-containing compounds as renin inhibitors [also seeHanson et al, Biochm. Biophys. Res. Comm., 132, 155-161 (1985), 146,959-963 (1987)]. EP Appl. #181,110, published 14 May 1986, describesdipeptide histidine derivatives as renin inhibitors. EP Appl. #186,977published 9 Jul. 1986 describes renin-inhibiting compounds containing analkynyl moiety, specifically a propargyl glycine moiety, attached to themain chain between the N-terminus and the C-terminus, such as N-[4(S)-[(N)-[bis(1-naphthylmethyl)acetyl]-DL-propargylglycylamino]-3(S)-hydroxy-6-methylheptanoyl]-L-isoleucinol. EP Appl. #189,203,published 30 Jul. 1986, describes peptidyl-aminodiols as renininhibitors. EP Appl. #200,406, published 10 Dec. 1986, describesalkylnaphthylmethylpropionyl-histidyl aminohydroxy alkanoates as renininhibitors. EP Appl. #216,539, published 1 Apr. 1987, describesalkylnaphthylmethylpropionyl aminoacyl aminoalkanoate compounds as renininhibitors orally administered for treatment of renin-associatedhypertension. PCT Application No. WO 87/04349, published 30 Jul. 1987,describes aminocarbonyl aminoacyl hydroxyether derivatives having analkylamino-containing terminal substituent and which are described ashaving renin-inhibiting activity for use in treating hypertension. EPAppl. #300,189 published 25 Jan. 1989 describes amino acid monohydricderivatives having an alkylamino-alkylamino N-terminus and aβ-alanine-histidine or sarcosyl-histidine attached to the main chainbetween the N-terminus and the C-terminus, which derivatives arementioned as useful in treating hypertension. U.S. Pat. No. 4,902,706which issued 13 Feb. 1990 describes a series ofhistidineamide-containing amino alkylaminocarbonyl-H-terminal aminodiolderivatives for use as renin inhibitors. U.S. Pat. No. 5,032,577 whichissued 16 Jul. 1991 describes a series ofhistidineamide-aminodiol-containing renin inhibitors.

[0007] Several classes of sulfonyl-containing amino-diol renin-inhibitorcompounds are known. For example, EP #229,667 published 22 Jul. 1987describes generally alkylsulfonyl histidineamide amino diolC-terminated-alkyl compounds as renin inhibitors. Australian PatentApplication #30797/89 published 7 Sep. 1989 describes alkylsulfonylhistineamide amino diol C-terminated-alkyl compounds as renininhibitors, such as(S)-α-[(S)-α-[(t-butyl-sulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3RS)-1-(cyclohexylmethyl)-2,3-dihydroxy-4,4-dimethylpentyl]-imidazole-4-propionamideand(S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S,4RS)-1-(cyclohexylmethyl)-2,3-dihydroxy-4-methylhexyl]imidazole-4-propionamide.U.S. Pat. No. 4,914,129 issued 3 Apr. 1990 describes sulfone-containingamino-hydroxyvaleryl compounds for use as antihypertensive agents, suchas the compoundsN-[2(S)-benzyl-3-tert-methylsulfonylpropionyl]-His-Cha-Val-n-butylamideand N-[2(R)-benzyl-3-tert-methylsulfonylpropionyl]-His-Cha-Val-n-butylamide. EP#416,373 published 13 Mar. 91 describes alkylsulfonyl histidineamideamino diol compounds as renin-inhibitors, such as(S)-α-[(S)-α-[(tert-butylsulfonyl)methyl]-hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-imidazol-4-propionamideand(S)-α-[(S)-α-[(tert-butylsulfonyl)methyl]-hydrocinnamamido]-N-[(1S,2R,3R/S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxybutyl]imidazol-4-propionamide.

[0008] Alkylaminoalkyl-terminated amino-diol renin-inhibitor compoundsare known. For example, U.S. Pat. No. 4,900,745 which issued 13 Feb.1990 describes poly (aminoalkyl)aminocarbonyl amino-diol amino acidderivatives as antihypertensive agents such asO-{N-[2-{N-[2-(N,N-dimethylamino)ethyl]-N-methylamino}-ethyl]-N-methylaminocarbonyl}-3-L-homophenyllactyl-α-(R)-ethyl-β-alanineamideof (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane andO-{N-[2-{N-[2-(N,N-dimethylamino)ethyl]-N-methylamino}-ethyl]-N-methylaminocarbonyl}-3-L-phenyllactyl-L-leucineamideof (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane. U.S.Pat. No. 4,902,706 which issued 20 Feb. 1990 describesaminoalkylaminocarbonyl amino-diol amino acid derivatives asantihypertensive agents such asO-{N-[2-(N,N-dimethylamino)ethyl]-N-methylaminocarbonyl}-3-L-homophenyllactyl-α-(R)-ethyl-β-alanineamideof (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane andO-{N-[2-(N,N-dimethylamino)ethyl]-N-methylaminocarbonyl-3-L-phenyllactyl-L-leucineamideof (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane.

[0009] Propargyl-group-containing amino-diol renin inhibitors are known.For example, U.S. Pat. No. 5,227,401 which issued 13 Jul. 1993 describesa series of ethynyl alanine amino diol compounds as renin inhibitors fortreatment of hypertension including, specifically, the compoundN1-[1R*-[[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]carbonyl]-3-butynyl-N4-[2-dimethyl-amino)ethyl]-N-4-methyl-2S*-(phenylmethyl)butanediamide.

DESCRIPTION OF THE INVENTION

[0010] Alkylaminoalkyl-terminated sulfide-sulfonyl-containing propargylamino diol compounds, having utility as renin inhibitors for treatmentof hypertension in a subject, constitute a family of compounds ofgeneral Formula I:

[0011] wherein each of R¹ and R¹¹ is a group independently selected fromhydrido, alkyl, alkylaminoalkyl and phenyl; wherein p is a numberselected from zero through five, inclusive; wherein r is a numberselected from zero, one and two; wherein R² is selected from hydrido andalkyl; wherein R³ is a group selected from hydrido, cycloalkylalkyl,aralkyl and haloaralkyl; wherein each of R⁴ and R⁶ is a groupindependently selected from hydrido and methyl; wherein R⁵ is apropargyl moeity or a propargyl-containing moiety selected from

[0012] wherein V is selected from hydrido, alkyl, cycloalkyl, aryl andaralkyl; wherein each of R⁹ and R¹⁰ is a group independently selectedfrom hydrido, alkyl, alkenyl, alkynyl, cycloalkyl and aryl; wherein m isa number selected from zero through three; wherein n is a numberselected from zero through three; wherein R⁷ is a group selected fromalkyl, cycloalkylalkyl and aralkyl; wherein R⁸ is a group selected fromhydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, alkenyl andhaloalkenyl; wherein each of R¹² and R¹³ is a group independentlyselected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkylacyl,aryl, aralkyl, haloaryl and haloaralkyl; and wherein any one of said R¹through R¹³ groups having a substitutable position may be substitutedwith one or more groups selected from alkyl, hydroxy, hydroxyalkyl,halo, alkoxy, alkoxyalkyl and alkenyl; or a pharmaceutically-acceptablesalt thereof.

[0013] A preferred family of compounds consists of compounds of FormulaI wherein each of R¹ and R¹¹ is independently selected from hydrido,methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl,N,N-diethylaminoethyl and phenyl; wherein p is a number selected fromzero through four, inclusive; wherein r is a number selected from zero,one and two; wherein R² is selected from hydrido and alkyl; wherein R³is selected from hydrido, cycloalkylalkyl, phenylalkyl, halophenylalkyl,naphthylalkyl and halonaphthylalkyl; wherein each of R⁴ and R⁶ isindependently selected from hydrido and methyl; wherein R⁵ is apropargyl moiety or a propargyl-containing moiety selected from

[0014] wherein V is selected from hydrido, alkyl, phenyl and benzyl;wherein each of R⁹ and R¹⁰ is independently. selected from hydrido,alkyl, alkenyl, alkynyl, cycloalkyl and aryl; wherein m is a numberselected from zero through three; wherein n is a number selected fromzero through three; wherein R⁷ is selected from cyclohexylmethyl andbenzyl, either one of which may be substituted with one or more groupsselected from alkyl, hydroxy and alkoxy; wherein R⁸ is selected fromhydrido, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkenyl andhaloalkenyl; and wherein each of R¹² and R¹³ is independently selectedfrom hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, halophenyl,phenylalkyl, halophenylalkyl, naphthyl, halonaphthyl, naphthylalkyl andhalonaphthylalkyl; or a pharmaceutically-acceptable salt thereof.

[0015] A more preferred family of compounds consists of compounds ofFormula I wherein each of R¹ and R¹¹ is independently selected fromhydrido, methyl, ethyl, n-propyl and isopropyl; wherein p is a numberselected from zero through three, inclusive; wherein r is a numberselected from zero, one and two; wherein R² is selected from hydrido,methyl, ethyl and n-propyl; wherein R³ is selected from hydrido,cyclohexylmethyl, benzyl, phenylethyl, fluorobenzyl, fluorophenylethyl,chlorobenzyl, chlorophenylethyl, naphthylmethyl, naphthylethyl,fluoronaphthylmethyl and chloronaphthylmethyl; wherein each of R⁴ and R⁶is independently selected from hydrido and methyl; wherein R⁵ is isselected from

[0016] wherein V is selected from hydrido and alkyl; wherein m is anumber selected from one through three; wherein R⁷ is cyclohexylmethyl;wherein R⁸ is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl,cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, allyl and vinyl;and wherein each of R¹² and R¹³ is independently selected from hydrido,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl,propylcarbonyl, ethylcarbonyl, methylcarbonyl, phenyl, benzyl,phenylethyl, monochlorophenyl, dichlorophenyl, monofluorophenyl,difluorophenyl, monochlorophenylmethyl, monochlorophenylethyl,dichlorophenylmethyl, dichlorophenylethyl, naphthyl, monofluoronaphthyl,monochloronaphthyl, naphthylmethyl, naphthylethyl, fluoronapthylmethyland chloronaphthylethyl; or a pharmaceutically-acceptable salt thereof.

[0017] An even more preferred family of compounds consists of compoundsFormula I wherein each of R¹ and R¹¹ is independently hydrido or methyl;wherein p is a number selected from zero through three, inclusive;wherein r is zero or two; wherein R² is selected from hydrido, methyl,ethyl and n-propyl; wherein R³ is selected from hydrido,cyclohexylmethyl, benzyl, phenylethyl, phenylpropyl, fluorobenzyl,fluorophenylethyl, chlorobenzyl, chlorophenylethyl, naphthylmethyl,naphthylethyl, fluoronaphthylmethyl and chloronaphthylmethyl; whereineach of R⁴ and R⁶ is hydrido; wherein R⁵ is selected fromcyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl,cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyland cyclohexylpropyl; wherein R⁷ is cyclohexylmethyl; wherein R⁸ isselected from

[0018] wherein V is selected from hydrido and alkyl; wherein m is one ortwo; wherein each of R⁹ and R¹⁰ is independently selected from hydrido,methyl, ethyl, n-propyl, isopropyl, cyclopropylmethyl, phenyl, benzyl,monochlorophenyl and dichlorophenyl; or a pharmaceutically-acceptablesalt thereof.

[0019] A highly preferred family of compounds consists of compounds ofFormula II:

[0020] wherein q is two or three; wherein r is zero or two; wherein R²is selected from hydrido, methyl, ethyl and phenyl; wherein R³ isselected from hydrido, cyclohexylmethyl, benzyl, fluorobenzyl,chlorobenzyl, fluoronaphthylmethyl and chloronaphthylmethyl; whereineach of R⁴ and R⁶ is hydrido; wherein R⁵ is selected from

[0021] wherein V is selected from hydrido and methyl; wherein m is oneor two; wherein R⁷ is cyclohexylmethyl; wherein R⁸ is selectedfrom.n-propyl, isobutyl, cyclopropyl, cyclopropylmethyl, allyl andvinyl; wherein each of R¹² and R¹³ is independently selected frommethyl, ethyl and isopropyl; or a pharmaceutically-acceptable saltthereof.

[0022] The term “hydrido” denotes a single hydrogen atom (H). Thishydrido group may be attached, for example, to an oxygen atom to form ahydroxyl group; or, as another example, one hydrido group may beattached to a carbon atom to form a

[0023] group; or, as another example, two hydrido groups may be attachedto a carbon atom to form a —CH₂— group. Where the term “alkyl” is used,either alone or within other terms such as “hydroxyalkyl”, the term“alkyl” embraces linear or branched radicals having one to about twentycarbon atoms or, preferably, one to about twelve carbon atoms. Morepreferred alkyl radicals are “lower alkyl” radicals having one to aboutten carbon atoms. Most preferred are lower alkyl radicals having one toabout six carbon atoms. The term “cycloalkyl” embraces cyclic radicalshaving three to about ten ring carbon atoms, preferably three to aboutsix carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl. The terms “alkylol”, and “hydroxyalkyl” embrace linear orbranched alkyl groups having one to about ten carbon atoms any one ofwhich may be substituted with one or more hydroxyl groups. The term“alkenyl” embraces linear or branched radicals having two to abouttwenty carbon atoms, preferably three to about ten carbon atoms, andcontaining at least one carbon-carbon double bond, which carbon-carbondouble bond may have either cis or trans geometry within the alkenylmoiety. The term “alkynyl” embraces linear or branched radicals havingtwo to about twenty carbon atoms, preferably two to about ten carbonatoms, and containing at least one carbon-carbon triple bond. The terms“alkoxy” and “alkoxyalkyl” embrace linear or branched oxy-containingradicals each having alkyl portions of one to about ten carbon atoms,such as methoxy group. The term “alkoxyalkyl” also embraces alkylradicals having two or more alkoxy groups attached to the alkyl radical,that is, to form monoalkoxyalkyl and dialkoxyalkyl groups. Preferredaryl groups are those consisting of one, two, or three benzene rings.The term “aryl” embraces aromatic radicals such as phenyl, naphthyl andbiphenyl. The term “aralkyl” embraces aryl-substituted alkyl radicalssuch as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl,phenylbutyl, diphenylethyl and napthylmethyl. The terms “benzyl” and“phenylmethyl” are interchangeable. Each of the terms sulfide, sulfinyl,and “sulfonyl”, whether used alone or linked to other terms, denotes,respectively, the divalent radicals

[0024] The term “alkenylalkyl” denotes a radical having a double-bondunsaturation site between two carbons, and which radical may consist ofonly two carbons or may be further substituted with alkyl groups whichmay optionally contain additional double-bond unsaturation. For any ofthe foregoing defined radicals, preferred radicals are those containingfrom one to about fifteen carbon atoms.

[0025] Specific examples of alkyl groups are methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl,isopentyl, methylbutyl, dimethylbutyl and neopentyl. Typical alkenyl andalkynyl groups may have one unsaturated bond, such as an allyl group, ormay have a plurality of unsaturated bonds, with such plurality of bondseither adjacent, such as allene-type structures, or in conjugation, orseparated by several saturated carbons.

[0026] Also included in the family of compounds of Formula I areisomeric forms, including diastereoisomers.

[0027] Compounds of Formula I would be useful to treat variouscirculatory-related disorders. As used herein, the term“circulatory-related” disorder is intended to embrace cardiovasculardisorders and disorders of the circulatory system, as well as disordersrelated to the circulatory system such as ophthalmic disorders,including glaucoma. In particular, compounds of Formula I would beuseful to inhibit enzymatic conversion of angiotensinogen to angiotensinI. When administered orally, a compound of Formula I would be expectedto inhibit plasma renin activity and, consequently, lower blood pressurein a patient such as a mammalian subject (e.g., a human subject). Thus,compounds of Formula I would be therapeutically useful in methods fortreating hypertension by administering to a hypertensive subject atherapeutically-effective amount of a compound of Formula I. The phrase“hypertensive subject” means, in this context, a subject suffering fromor afflicted with the effects of hypertension or susceptible to ahypertensive condition if not treated to prevent or control suchhypertension. Other examples of circulatory-related disorders whichcould be treated by compounds of the invention include congestive heartfailure, renal failure and glaucoma.

Description of the Synthetic Methods for the Preparation of the ReninInhibitors of the Invention

[0028]

[0029] wherein R¹ through R¹³, r and p are as defined above.

[0030] A suitably protected amino aldehyde 1 is treated with a Grignardreagent or other organometallic reagent, preferably vinylmagnesiumbromide, to obtain the vinyl carbinol 2. This material, suitablyprotected, is oxidized, preferably with ozone, followed by dimethylsulfide or zinc treatment, to give intermediate 3. The preceedingprocess is exemplified in Hanson et al, J. Org. Chem., 50, 5399 (1985).This aldehyde is reacted with an organometallic reagent such asisobutylmagnesium chloride to give intermediate 4. Compound 4 isdeprotected then coupled, using standard amide/peptide couplingmethodology to protected cycloalkylalkyl-containing amino acidderivatives 5 to give compound 6. These standard coupling proceduressuch as the carbodiimide, active ester (N-hydroxysuccinimide), and mixedcarbonic anhydride methods are shown in Benoiton et al, J. Org. Chem.,48, 2939 (1983) and Bodansky et al, “Peptide Synthesis”, Wiley (1976).Cyclopropylmethyl-containing amino acid derivatives may be prepared bycyclopropanation of allylglycine using procedures such as found inVorbruggen, Tetrahedron Letters, 9, 629 (1975). Intermediate 6 is thendeprotected, then coupled to intermediate 7 or 11 or 12 using thestandard amide/peptide coupling methodology, to give compounds ofFormula I. Suitable protecting groups may be selected from among thosereviewed by R. Geiger in “The Peptides”, Academic Press, N.Y. vol. 2(1979). For example, P₁ or P₃ may be Boc or Cbz; P₂ may be a typicaloxygen protective group such as acetyl or t-butyldimethylsilyl.

[0031] wherein R¹-R³, R⁹-R¹³ and p are as defined above and R^(a) islower alkyl or benzyl.

[0032] Intermediate 7 may be prepared according to Synthetic Scheme 2.1,4 addition of a suitable thiol 9 to a suitable acrylic acid benzylester 8 in the presence of base catalysts such as triethyl amine orbenzyltrimethylammonium hydroxide, afforded α, β disubstitutedthio-propionic acid alkyl esters 10. In the case of R²=H, a suitablemalonic acid dialkyl ester is hydrolyzed to a mono ester, followed byconcomitant decarboxylative dehydration to provide α substituted acrylicacid alkyl ester. Compound 10 is converted into its correspondingthio-propionic acid 11 via debenzylation. Compound 11 then is furtherconverted into either its corresponding sulfoxide 12 or sulfone 7 viaoxidation with 3-chloroperbenzoic acid or potassium peroxomonosulfaterespectively.

[0033] Abbreviations: P₁ is an N-protecting group; P₂ is H or an oxygenprotecting group; P₃ is an N-protecting group.

[0034] The following Steps 1-13 constitute specific exemplification ofmethods to prepare starting materials and intermediates embraced by theforegoing generic synthetic schemes. Those skilled in the art willreadily understand that known variations of the conditions and processesof the following preparative procedures can be used to prepare thecompounds of Steps 1-13. All temperatures expressed are in degreesCentigrade. Compounds of Examples 1-13 may be prepared by using theprocedures described in the following Steps 1-13:

[0035] Step 1: Preparation of(2R,3S)-N-[(tert-Butyloxy)carbonyl]-3-amino-2-acetoxy-4-phenylbutanal

[0036] Ozone/oxygen was bubbled at −70° C. into a solution of(3S,4S)-N-[(tert-Butyloxy)carbonyl]-4-amino-3-acetoxy-5-phenylpentene(2.55 g, 8.0 mmol) [prepared by the method of Hanson et al, J. Org.Chem., 50, 5399 (1985)] in 100 mL of methylene chloride until a deepblue color persisted. Oxygen was introduced until the blue colorcompletely faded, then 3.0 mL of Me₂S was added and the solution wasallowed to warm to 0-5° C. and stand overnight. The solvent was removedat 0° C. under vacuum yielding the title compound as a thick yellow oilwhich was used in the following step without purification.

[0037] Step 2: Preparation of(2S,3R,4S)-N-[(tert-Butyloxy)carbonyl]-2-amino-1-phenyl-3,4-dihydroxy-6-methylheptane

[0038] The oil prepared in Step 1 was dissolved under nitrogen in 100 mLof dry THF and cooled to -70° C. To this solution was added 13 mL (26mmol) of a 2.0M solution of isobutylmagnesium chloride in ether and thestirred mixture was allowed to warm to room temperature and stir for 2hrs. After decomposition with MeOH/H₂O the mixture was diluted withether, washed with saturated NH₄Cl solution twice, then dried and thesolvents stripped off under vacuum. The residue was allowed to standovernight in 80% MeOH-H₂O containing excess ammonium hydroxide. The MeOHwas stripped off and the mixture was extracted with ether. Theseextracts were combined, washed with water, dilute KHSO₄, then dried andevaporated to give 2.36 g of a yellow glass which crystallized from 50mL of pentane on standing overnight. The yellow-white powder obtainedwas recrystallized from ether-hexane and furnished the title compound(0.41 g) as white, hairy needles, mp 134-136° C., Rf (ether): singlespot, 0.6. By chromatography of the mother liquors and crystallizationof the appropriate fractions, an additional 0.22 g of product, mp138-139° C., was obtained. Anal: Calcd. for C₁₉H₃₁NO₄ (337.45): C,67.62; H, 9.26; N, 4.15. Found: C, 67.51; H, 9.43; N, 4.24.

[0039] Step 3: Preparation of(2S,3R,4S)-N-[(tert-Butyloxy)carbonyl]-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

[0040] The diol of Step 2, 0.27 g, was reduced in MeOH with 60 psi H₂ at60° C. in 3 hrs using 5% Rh/C catalyst. After filtering, the solvent wasstripped off and the white crystals were recrystallized fromCH₂Cl₂-hexane to furnish tiny needles of the title compound, 0.19 g, mp126-128° C.; further recrystallization gave mp 128.5-129.5° C. Rf(ether): single spot, 0.8. Anal: Calcd. for C₁₉H₃₇NO₄ (343.50): C,66.43; H, 10.86, N, 4.08. Found: C, 66.43; H, 11.01; N. 4.03.

[0041] Step 4: Preparation of(2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

[0042] The title compound of Step 3 (10 g) was dissolved 6.9N HCl indioxane (300 mL). The mixture was stirred for 30 minutes at roomtemperature. The solvent was removed in vacuo and to the residue wasadded 5% aqueous sodium hydroxide (30 mL) until a pH of 14 was obtained.This mixture was extracted with ether and the ether extract was washedwith water and brine, then the solvent was evaporated to give the titlecompound (7.3 g, 100% yield). ¹H NMR: 300 MHz spectrum consistent withproposed structure. Anal: calcd. for C₁₄H₂₉NO₂: C, 69.07; H, 12.01; N,5.78. Found: C, 69.19; H, 12.34; N, 5.78.

[0043] Step 5: L-Boc-C-propargylglycine

[0044] L-C-Propargylglycine (10 g) [prepared by the method of Schwyzeret al., Helv. Chim. Acta 59, 2181 (1976)] was suspended intetrahydrofuran (30 mL). Water (30 mL), potassium carbonate (36.7 g),and di-tert-butyl-dicarbonate (21.9 g) were added. Additional water wasadded to produce a solution which was stirred for 12 hours at roomtemperature. The organic solvent was then evaporated and the aqueoussolution was washed with ether, then acidified to pH 3 with IN aqueouscitric acid. The solution was extracted with methylene chloride and thesolvent evaporated to give the title compound (18.9 g, 97% yield), usedwithout further purification.

[0045] Step 6: Preparation of Boc L-C-propargylglycine amide of(2S,3R,4S) 2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

[0046] Boc L-C-propargylglycine (1.2 g) was dissolved in methylenechloride (5 mL) and N-methyl piperidine (0.57 g) was added. The mixturewas cooled to zero degrees centigrade and isobutyl chloroformate (0.78g) was added. The mixture was stirred for 10 minutes whereupon the titlecompound of Step 4 (1.4 g) in methylene chloride (5 mL) was added andthis mixture stirred for 15 minutes at 0° C. and 4° C. for 12 hours. Thereaction mixture was washed successively with IN citric acid, saturatedsodium hydrogen carbonate, water and brine. The organic layer was driedover magnesium sulfate and evaporated to dryness. The residue waschromatographed on silica gel to give the title compound as a colorlessoil. 300 MHz ¹H NMR: consistent with proposed structure.

[0047] Step 7: Preparation of L-C-propargylglycine amide of (2S,3R,4S)2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

[0048] The title compound of Step 6 (0.76 g) was dissolved in a mixtureof trifluoroacetic acid (4.9 mL) and methylene chloride (4.9 mL), andstirred for 30 minutes at room temperature. The solvent was thenevaporated and the residue taken up in ethyl acetate. The organic layerwas washed with saturated sodium hydrogen carbonate, water and brine,then dried over magnesium sulfate and evaporated to give the titleamine. 300 MHz ¹H NMR: consistent with proposed structure.

[0049] Step 8: Preparation of ethyl α-methylenebenzenepropanoate

[0050] A mixture of of KOH (8.5 g) in ethanol (100 mL) was added at roomtemperature to benzylmalonic acid diethyl ester (40 g) in ethanol (80mL) and the solution was stirred at room temperature overnight, thenconcentrated by evaporation. Water (14 mL) was added and then themixture was acidified in an ice bath with concentrated hydrochloric acid(12.6 mL). The mixture was-partitioned between water and ether; theorganic phase was separated, dried and the ether was evaporated. Theresidue was treated with pyridine (26 mL), piperidine (1.22 g) andparaformaldehyde (3.56 g). The mixture was heated in an oil bath (130°)for 90 minutes, then cooled, and water (440 mL) was added. The mixturewas extracted 3 times with n-hexane (150 mL). The combined organicphases were washed successively with water, 1N HCl, water, saturatedNaHCO₃ solution and brine. The organic solution was dried (MgSO₄) andevaporated to give the title compound as colorless oil (26 g, 85%yield). ¹H NMR: 300 MHz spectrum consistent with proposed structure.

[0051] Step 9: Preparation of α-methylenebenzenepropanoic acid

[0052] The ethyl α-methylenebenzenepropanoate of Step 8 (4.6 g, 24.3mmol) was dissolved in methanol (12 mL) and then reacted with 2Npotassium hydroxide (24 mL) solution. The mixture was stirred at roomtemperature for 4 hours and concentrated by evaporation. The residue wasdiluted with water and washed with ether. The aqueous layer wasacidified to pH 2 with 1N HCl, and then extracted with ethyl acetate.The extracts were dried (MgSO₄) and evaporated to give the titlecompound as colorless oil (2.8 g, 66% yield). ¹H NMR: 300 MHz spectrumconsistent with proposed structure.

[0053] Step 10: Preparation of phenylmethyl α-methylenebenzenepropanoate

[0054] The title acid of Step 9 (5.2 g, 30 mmol) was dissolved indimethylformamide (25 mL) and cooled to 0° C. To this solution potassiumcarbonate (5.7 g, 41.48 mmol) was added followed by benzyl bromide (5.7g, 29.7 mmol). The mixture was stirred at room temperature overnight.The mixture was filtered and the filtrate was diluted with ethylacetate, washed with 3 times of water, brine. The solution was dried(Na₂SO₄) and evaporated. The residue was purified by flashchromatography on silica gel, eluting with 90:10 heptane:ethyl acetateto give the pure title compound as colorless oil (4.5 g, 60% yield). ¹HNMR: 300 MHz spectrum consistent with proposed structure. Anal: calcd.for C₁₇H₁₆O₂: C, 80.93; H, 6.39. Found: C, 80.69; H, 6.47.

[0055] Step 11: Preparation of phenylmethylα-[[[2-(dimethylamino)ethyl]thio]methyl]benzene-propanoate

[0056] The title compound of Step 10 (1.5 g, 5.95 mmol) was dissolvedunder argon in methanol (22 mL). To this solution was added2-dimethylaminoethanethiol hydrochloride (843 mg, 5.95 mmol), piperidine(0.78 mL, 7.85 mmol) and benzyltrimethylammonium hydroxide (0.25 mL, 0.6mmol), and the mixture was stirred at room temperature for 16 hours. Thesolvent was removed on a rotary evaporator and then the residue waspurified by flash chromatography on silica gel, eluting with 20:1CH₂Cl₂:MeOH to give the pure title compound (0.5 g, 24% yield). ¹H NMR:300 MHz spectrum consistent with proposed structure. Anal: calcd. forC₂₁H₂₇NO₂S+0.2H₂O: C, 69.85; H, 7.65; N, 3.88. Found: C, 69.58; H, 7.60;N, 3.98.

[0057] Step 12: Preparation of phenylmethylα-[[[2-(dimethylamino)ethyl]sulfonyl]methyl]benzene-propanoate

[0058] The title compound in Step 11 (0.5 g, 1.4 mmol) was dissolved inmethanol (7 mL) and, while cooling with ice, potassium peroxomonosulfate(1.3 g) in water (6 mL) was added and the mixture was stirred at roomtemperature overnight. The solution was diluted with water and extractedwith methylene chloride, and the extracts were dried (Na₂SO₄) andconcentrated by evaporation. The residue was purified by flashchromatography on silica gel, eluting with 20:1 CH₂Cl₂-MeOH to give puretitle compound as white powder (400 mg, 73%). ¹H NMR: 300 MHz spectrumconsistent with proposed structure. Anal: calcd. for C₂₁H₂₇NO₄S: C,64.76; H, 6.99; N, 3.60. Found: C, 64.01; H, 6.88; N, 3.41.

[0059] Step 13: Preparation ofα-[[[2-(dimethylamino)ethyl]sulfonyl]methyl]benzeneprop-anoic acid

[0060] The title compound of Step 12 (150 mg, 0.4 mmol) was debenzylatedin ethanol with 5 psi H₂ at room temperature for 1.5 hours using 4% Pd/Ccatalyst. After filtering, the solvent was stripped off to give thetitle compound as white powder (110 mg, 70% yield). ¹H NMR: 300 MHzspectrum consistent with proposed structure. Anal. calcd. forC₁₄H₂₁NO₄S: C, 56.16; H, 7.07; N, 4.68. Found: C, 55.88; H, 6.99; N,4.35.

[0061] The following working Examples are provided to illustratesynthesis of Compounds 1-13 of the present invention and are notintended to limit the scope thereof. Those skilled in the art willreadily understand that known variations of the conditions and processesof the following preparative procedures can be used to prepare thecompounds of the Examples. All temperatures expressed are in degreesCentigrade.

EXAMPLE 1

[0062]

[0063]N-[1R*-[[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]carbonyl]-3-butynyl]-αR*-[[[2-(dimethylamino)ethyl]sulfonyl]methyl]benzenepropana-mide

[0064] The title acid of Step 13 is mixed with dry dimethylformamide andstirred at room temperature. To this is added solid N,N′-disuccinimidylcarbonate, followed by pyridine, and finally a solution ofdimethylaminopyridine in dimethylformamide. Four hours later, the titleamine of Step 7 is added as a solid. The mixture is stirred for 2 daysat room temperature. The solvent is then evaporated and the residuetaken up in ethyl acetate, washing this layer four times with 5% aqueouspotassium carbonate. The organic layer is dried and evaporated to a paleyellow foam. This foam is chromatographed on silica gel, eluting with10% methanol in methylene chloride containing 1% ammonium hydroxide, togive the pure title compound.

BIOLOGICAL EVALUATION Human Renin Inhibition in Vitro

[0065] Compounds of Formula I may be evaluated as inhibitors of humanrenin in an in vitro assay, as follows: This human renin inhibition testhas been previously described in detail [Papaioannou et al., Clinicaland Experimental Hypertension, A7 (9), 1243-1257 (1985)]. Human renin isobtained from the National Institute for Biological Standards, London.An incubation mixture is prepared containing the following components:in a total volume of 0.25 mL: 100 mM Tris-acetate buffer at pH 7.4, 25×10⁻⁶ Goldblatt units of renin, 0.05 mL of plasma from human volunteerstaking oral contraceptives, 6.0 mM Na-EDTA, 2.4 mM phenylmethyl sulfonylfluoride, 1.5 mM 8-hydroxyquinoline, 0.4 mg/mL bovine serum albumin(BSA), and 0.024 mg/mL neomycin sulfate. This mixture is incubated fortwo hours at 37° C. in the presence or absence of renin inhibitors. Theproduced angiotensin I is determined by radioimmunoassay (New EnglandNuclear kit). Test compounds to be assayed are dissolved in DMSO anddiluted with 100 mM Tris-acetate buffer at pH 7.4 containing 0.5% BSA tothe appropriate concentration. The final concentration of organicsolvent in the reaction mixture is less than 1%. Control incubations at37° C. are used to correct for effects of organic solvent on reninactivity. The in vitro enzymatic conversion of angiotensinogen toangiotensin I would be expected to be inhibited by test compound of theinvention.

[0066] Also embraced within this invention is a class of pharmaceuticalcompositions comprising one or more compounds of Formula I inassociation with one or more non-toxic, pharmaceutically acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as “carrier” materials) and, if desired, other activeingredients. The compounds of the present invention may be administeredby any suitable route, preferably in the form of a pharmaceuticalcomposition adapted to such a route, and in a dose effective for thetreatment intended. Therapeutically effective doses of the compounds ofthe present invention required to prevent or arrest the progress of themedical condition are readily ascertained by one of ordinary skill inthe art. The compounds and composition may, for example, be administeredintra-vascularly, intraperitoneally, subcutaneously, intra-muscularly ortopically.

[0067] For oral administration, the pharmaceutical composition may be inthe form of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. These may with advantagecontain an amount of active ingredient from about 1 to 250 mg,preferably from about 25 to 150 mg. A suitable daily dose for a mammalmay vary widely depending on the condition of the patient and otherfactors. However, a dose of from about 0.1 to 3000 mg/kg body weight,particularly from about 1 to 100 mg/kg body weight, may be appropriate.

[0068] The active ingredient may also be administered by injection as acomposition wherein, for example, saline, dextrose or water may be usedas a suitable carrier. A suitable daily dose is from about 0.1 to 100mg/kg body weight injected per day in multiple doses depending on thedisease being treated. A preferred daily dose would be from about 1 to30 mg/kg body weight. Compounds indicated for prophylactic therapy willpreferably be administered in a daily dose generally in a range fromabout 0.1 mg to about 100 mg per kilogram of body weight per day. A morepreferred dosage will be a range from about 1 mg to about 100 mg perkilogram of body weight. Most preferred is a dosage in a range fromabout 1 to about 50 mg per kilogram of body weight per day. A suitabledose can be administered, in multiple sub-doses per day. These sub-dosesmay be administered in unit dosage forms. Typically, a dose or sub-dosemay contain from about 1 mg to about 400 mg of active compound per unitdosage form. A more preferred dosage will contain from about 2 mg toabout 200 mg of active compound per unit dosage form. Most preferred isa dosage form containing from about 3 mg to about 100 mg of activecompound per unit dose.

[0069] The dosage regimen for treating a disease condition with thecompounds and/or compositions of this invention is selected inaccordance with a variety of factors, including the type, age, weight,sex and medical condition of the patient, the severity of the disease,the route of administration, and the particular compound employed, andthus may vary widely.

[0070] For therapeutic purposes, the compounds of this invention areordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered per os, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules having one or more of the carriers or diluents mentioned foruse in the formulations for oral administration. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, and/or various buffers. Other adjuvants and modes ofadministration are well and widely known in the pharmaceutical art.

[0071] Although this invention has been described with respect tospecific embodiments, the details of these embodiments are not to beconstrued as limitations.

What is claimed is:
 1. A compound of Formula I:

wherein each of R¹ and R¹¹ is a group independently selected fromhydrido, alkyl, alkylaminoalkyl and phenyl; wherein p is a numberselected from zero through five, inclusive; wherein r is a numberselected from zero, one and two; wherein R² is selected from hydrido andalkyl; wherein R³ is a group selected from hydrido, cycloalkylalkyl,aralkyl and haloaralkyl; wherein each of R⁴ and R⁶ is a groupindependently selected from hydrido and methyl; wherein R⁵ is selectedfrom

wherein V is selected from hydrido, alkyl, cycloalkyl, aryl and aralkyl;wherein each of R⁹ and R¹⁰ is a group independently selected fromhydrido, alkyl, alkenyl, alkynyl, cycloalkyl and aryl; wherein m is anumber selected from zero through three; wherein n is a number selectedfrom zero through three; wherein R⁷ is a group selected from alkyl,cycloalkylalkyl and aralkyl; wherein R⁸ is a group selected fromhydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, alkenyl andhaloalkenyl; wherein each of R¹² and R¹³ is a group independentlyselected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkylacyl,aryl, aralkyl, haloaryl and haloaralkyl; and wherein any one of said R¹through R¹³ groups having a substitutable position may be substitutedwith one or more groups selected from alkyl, hydroxy, hydroxyalkyl,halo, alkoxy, alkoxyalkyl and alkenyl; or a pharmaceutically-acceptablesalt thereof.
 2. Compound of claim 1 wherein each of R¹ and R¹¹ isindependently selected from hydrido, methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, N,N′-dimethylaminomethyl,N,N′-diethylaminomethyl, N,N′diethylaminoethyl and phenyl; wherein p isa number selected from zero through four, inclusive; wherein r is anumber selected from zero, one and two; wherein R² is selected fromhydrido and alkyl; wherein R³ is selected from hydrido, cycloalkylalkyl,phenylalkyl, halophenylalkyl, naphthylalkyl and halonaphthylalkyl;wherein each of R⁴ and R⁶ is independently selected from hydrido andmethyl; wherein R⁵ is selected from

wherein V is selected from hydrido, alkyl, phenyl and benzyl; whereineach of R⁹ and R¹⁰ is independently selected from hydrido, alkyl,alkenyl, alkynyl, cycloalkyl and aryl; wherein m is a number selectedfrom zero through three; wherein n is a number selected from zerothrough three; wherein R⁷ is selected from cyclohexylmethyl and benzyl,either one of which may be substituted with one or more groups selectedfrom alkyl, hydroxy and alkoxy; wherein R⁸ is selected from hydrido,alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkenyl andhaloalkenyl; and wherein each of R¹² and R¹³ is independently selectedfrom hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, halophenyl,phenylalkyl, halophenylalkyl, naphthyl, halonaphthyl, naphthylalkyl andhalonaphthylalkyl; or a pharmaceutically-acceptable salt thereof. 3.Compound of claim 2 wherein each of R¹ and R¹¹ is independently selectedfrom hydrido, methyl, ethyl, n-propyl and isopropyl; wherein p is anumber selected from zero through three, inclusive; wherein r is anumber selected from zero, one and two; wherein R² is selected fromhydrido, methyl, ethyl and n-propyl; wherein R³ is selected fromhydrido, cyclohexylmethyl, benzyl, phenylethyl, fluorobenzyl,fluorophenylethyl, chlorobenzyl, chlorophenylethyl, naphthylmethyl,naphthylethyl, fluoronaphthylmethyl and chlronaphthylmethyl; whereineach of R⁴ and R⁶ is independently selected from hydrido and methyl;wherein R⁵ is selected-from

wherein V is selected from hydrido, alkyl, cycloalkyl, aryl and aralkyl;wherein m is a number selected from one through three; wherein R⁷ iscyclohexylmethyl; wherein R⁸ is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl,cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, allyland vinyl; and wherein each of R¹² and R¹³ is independently selectedfrom hydrido, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl,propylcarbonyl, ethylcarbonyl, methylcarbonyl, phenyl, benzyl,phenylethyl, monochlorophenyl, dichlorophenyl, monofluorophenyl,difluorophenyl, monochlorophenylmethyl, monochlorophenylethyl,dichlorophenylmethyl, dichlorophenylethyl, naphthyl, monofluoronaphthyl,monochloronaphthyl, naphthylmethyl, naphthylethyl, fluoronapthylmethyland chloronaphthylethyl; or a pharmaceutically-acceptable salt thereof.4. Compound of claim 3 wherein each of R¹ and R¹¹ is independentlyhydrido or methyl; wherein p is a number selected from zero throughthree, inclusive; wherein r is zero or two; wherein R² is selected fromhydrido, methyl, ethyl and n-propyl; wherein R³ is selected fromhydrido, cyclohexylmethyl, benzyl, phenylethyl, phenylpropyl,fluorobenzyl, fluorophenylethyl, chlorobenzyl, chlorophenylethyl,naphthylmethyl, naphthylethyl, fluoronaphthylmethyl andchloronaphthylmethyl; wherein each of R⁴ and R⁶ is hydrido; wherein R⁵is selected from

wherein V is selected from hydrido and methyl; wherein m is one or two;wherein R⁷ is cyclohexylmethyl; wherein R⁸ is selected from ethyl,n-propyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopropylmethyl,allyl and vinyl; wherein each of R¹² and R¹³ is independently selectedfrom hydrido, methyl, ethyl, n-propyl, isopropyl, cyclopropylmethyl,phenyl, benzyl, monochlorophenyl and dichlorophenyl; or apharmaceutically-acceptable salt thereof.
 5. Compound of claim 4 ofFormula II

wherein r is zero or two; wherein q is two or three; wherein R² isselected from hydrido, methyl, ethyl and phenyl; wherein R³ is selectedfrom hydrido, cyclohexylmethyl, benzyl, fluorobenzyl, chlorobenzyl,fluoronaphthylmethyl and chloronaphthylmethyl; wherein each of R⁴ and R⁶is hydrido; wherein R⁵ is selected from

wherein V is selected from hydrido and methyl; wherein m is one or two;wherein R⁷ is cyclohexylmethyl; wherein R⁸ is selected from n-propyl,isobutyl, cyclopropyl, cyclopropylmethyl, allyl and vinyl; wherein R¹²and R¹³ is independently selected from methyl, ethyl and isopropyl; or apharmaceutically-acceptable salt thereof.
 6. Compound of claim 5selected from compounds, their tautomers and pharmaceutically-acceptablesalts thereof, of the group consisting of:


7. Compound of claim 6 which isN-[1R*-[[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]carbonyl]-3-butynyl]-αR*-[[[2-(dimethylamino)ethyl]sulfonyl]methyl]benzenepropana-mideor a pharmaceutically-acceptalble salt thereof.
 8. A pharmaceuticalcomposition comprising a therapeutically-effective amount of arenin-inhibiting compound and a pharmaceutically-acceptable carrier ordiluent, said renin-inhibiting compound selected from a family ofcompounds of Formula I:

wherein each of R¹ and R¹¹ is a group independently selected fromhydrido, alkyl, alkylaminoalkyl and phenyl; wherein p is a numberselected from zero through five, inclusive; wherein r is a numberselected from zero, one and two; wherein R² is selected from hydrido andalkyl; wherein R³ is a group selected from hydrido, cycloalkylalkyl,aralkyl and haloaralkyl; wherein each of R⁴ and R⁶ is a groupindependently selected from hydrido and methyl; wherein R⁵ is selectedfrom

wherein V is selected from hydrido, alkyl, cycloalkyl, aryl and aralkyl;wherein each of R⁹ and R¹⁰ is a group independently selected fromhydrido, alkyl, alkenyl, alkynyl, cycloalkyl and aryl; wherein m is anumber selected from zero through three; wherein n is a number selectedfrom zero through three; wherein R⁷ is a group selected from alkyl,cycloalkylalkyl and aralkyl; wherein R⁸ is a group selected fromhydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, alkenyl andhaloalkenyl; wherein each of R¹² and R¹³ is a group independentlyselected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkylacyl,aryl, aralkyl, haloaryl and haloaralkyl; and wherein any one of said R¹through R¹³ groups having a substitutable position may be substitutedwith one or more groups selected from alkyl, hydroxy, hydroxyalkyl,halo, alkoxy, alkoxyalkyl and alkenyl; or a pharmaceutically-acceptablesalt thereof.
 9. The composition of claim 8 wherein each of R¹ and R¹¹is independently selected from hydrido, methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,N,N′-dimethylaminomethyl, N,N′-diethylaminomethyl, N,N′diethylaminoethyland phenyl; wherein p is a number selected from zero through four,inclusive; wherein r is a number selected from zero, one and two;wherein R² is selected from hydrido and alkyl; wherein R³ is selectedfrom hydrido, cycloalkylalkyl, phenylalkyl, halophenylalkyl,naphthylalkyl and halonaphthylalkyl; wherein each of R⁴ and R⁶ isindependently selected from hydrido and methyl; wherein R⁵ is selectedfrom

wherein V is selected from hydrido, alkyl, phenyl and benzyl; whereineach of R⁹ and R¹⁰ is independently selected from hydrido, alkyl,alkenyl, alkynyl, cycloalkyl and aryl; wherein m is a number selectedfrom zero through three; wherein n is a number selected from zerothrough three; wherein R⁷ is selected from cyclohexylmethyl and benzyl,either one of which may be substituted with one or more groups selectedfrom alkyl, hydroxy and alkoxy; wherein R⁸ is selected from hydrido,alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkenyl andhaloalkenyl; and wherein each of R¹² and R¹³ is independently selectedfrom hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, halophenyl,phenylalkyl, halophenylalkyl, naphthyl, halonaphthyl, naphthylalkyl andhalonaphthylalkyl; or a pharmaceutically-acceptable salt thereof. 10.The composition of claim 9 wherein each of R¹ and R¹¹ is independentlyselected from hydrido, methyl, ethyl, n-propyl and isopropyl; wherein pis a number selected from zero through three, inclusive; wherein r is anumber selected from zero, one and two; wherein R² is selected fromhydrido, methyl, ethyl and n-propyl; wherein R³ is selected fromhydrido, cyclohexylmethyl, benzyl, phenylethyl, fluorobenzyl,fluorophenylethyl, chlorobenzyl, chlorophenylethyl, naphthylmethyl,naphthylethyl, fluoronaphthylmethyl and chloronaphthylmethyl; whereineach of R⁴ and R⁶ is independently selected from hydrido and methyl;wherein R⁵ is selected from

wherein V is selected from hydrido, alkyl, cycloalkyl, aryl and aralkyl;wherein m is a number selected from one through three; wherein R⁷ iscyclohexylmethyl; wherein R⁸ is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl,cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, allyland vinyl; and wherein each of R¹² and R¹³ is independently selectedfrom hydrido, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl,propylcarbonyl, ethylcarbonyl, methylcarbonyl, phenyl, benzyl,phenylethyl, monochlorophenyl, dichlorophenyl, monofluorophenyl,difluorophenyl, monochlorophenylmethyl, monochlorophenylethyl,dichlorophenylmethyl, dichlorophenylethyl, naphthyl, monofluoronaphthyl,monochloronaphthyl, naphthylmethyl, naphthylethyl, fluoronapthylmethyland chloronaphthylethyl; or a pharmaceutically-acceptable salt thereof.11. The composition of claim 10 wherein each of R¹ and R¹¹ isindependently hydrido or methyl; wherein p is a number selected fromzero through three, inclusive; wherein r is zero or two; wherein R² isselected from hydrido, methyl, ethyl and n-propyl; wherein R³ isselected from hydrido, cyclohexylmethyl, benzyl, phenylethyl,phenylpropyl, fluorobenzyl, fluorophenylethyl, chlorobenzyl,chlorophenylethyl, naphthylmethyl, naphthylethyl, fluoronaphthylmethyland chloronaphthylmethyl; wherein each of R⁴ and R⁶ is hydrido; whereinR⁵ is selected from

wherein V is selected from hydrido and methyl; wherein m is one or two;wherein R⁷ is cyclohexylmethyl; wherein R⁸ is selected from ethyl,n-propyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopropylmethyl,allyl and vinyl; wherein each of R¹² and R¹³ is independently selectedfrom hydrido, methyl, ethyl, n-propyl, isopropyl, cyclopropylmethyl,phenyl, benzyl, monochlorophenyl and dichlorophenyl; or apharmaceutically-acceptable salt thereof.
 12. The composition of claim11 wherein said compound is of Formula II

wherein r is zero or two; wherein q is two or three; wherein R² isselected from hydrido, methyl, ethyl and phenyl; wherein R³ is selectedfrom hydrido, cyclohexylmethyl, benzyl, fluorobenzyl, chlorobenzyl,fluoronaphthylmethyl and chloronaphthylmethyl; wherein each of R⁴ and R⁶is hydrido; wherein R⁵ is selected from

wherein V is selected from hydrido and methyl; wherein m is one or two;wherein R⁷ is cyclohexylmethyl; wherein R⁸ is selected from n-propyl,isobutyl, cyclopropyl, cyclopropylmethyl, allyl and vinyl; wherein R¹²and R¹³ is independently selected from methyl, ethyl and isopropyl; or apharmaceutically-acceptable salt thereof.
 13. The composition of claim12 wherein said renin inhibitor compound is selected from compounds,their tautomers and pharmaceutically-acceptable salts thereof, of thegroup consisting of:


14. The composition of claim 13 wherein said renin-inhibitor compound isN-[1R*-[[[1S, 1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]carbonyl]-3-butynyl]-αR*-[[[2-dimethylamino)ethyl]sulfonyl]methyl]benzenepropana-mide.15. A therapeutic method for treating hypertension or glaucoma, saidmethod comprising administering to a hypertensive patient atherapeutically-effective amount of a compound of Formula I:

wherein each of R¹ and R¹¹ is a group independently selected fromhydrido, alkyl, alkylaminoalkyl and phenyl; wherein p is a numberselected from zero through five, inclusive; wherein r is a numberselected from zero, one and two; wherein R² is selected from hydrido andalkyl; wherein R³ is a group selected from hydrido, cycloalkylalkyl,aralkyl and haloaralkyl; wherein each of R⁴ and R⁶ is a groupindependently selected from hydrido and methyl; wherein R⁵ is selectedfrom

wherein V is selected from hydrido, alkyl, cycloalkyl, aryl and aralkyl;wherein each of R⁹ and R¹⁰ is a group independently selected fromhydrido, alkyl, alkenyl, alkynyl, cycloalkyl and aryl; wherein m is anumber selected from zero through three; wherein n is a number selectedfrom zero through three; wherein R⁷ is a group selected from alkyl,cycloalkylalkyl and aralkyl; wherein R⁸ is a group selected fromhydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, alkenyl andhaloalkenyl; wherein each of R¹² and R¹³ is a group independentlyselected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkylacyl,aryl, aralkyl, haloaryl and haloaralkyl; and wherein any one of said R¹through R¹³ groups having a substitutable position may be substitutedwith one or more groups selected from alkyl, hydroxy, hydroxyalkyl,halo, alkoxy, alkoxyalkyl and alkenyl; or a pharmaceutically-acceptablesalt thereof.
 16. The method of claim 15 wherein each of R¹ and R¹¹ isindependently selected from hydrido, methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, N,N′-dimethylaminomethyl,N,N′-diethylaminomethyl, N,N′diethylaminoethyl and phenyl; wherein p isa number selected from zero through four, inclusive; wherein r is anumber selected from zero, one and two; wherein R² is selected fromhydrido and alkyl; wherein R³ is selected from hydrido, cycloalkylalkyl,phenylalkyl, halophenylalkyl, naphthylalkyl and halonaphthylalkyl;wherein each of R⁴ and R⁶ is independently selected from hydrido andmethyl; wherein R⁵ is selected from

wherein V is selected from hydrido, alkyl, phenyl and benzyl; whereineach of R⁹ and R¹⁰ is independently selected from hydrido, alkyl,alkenyl, alkynyl, cycloalkyl and aryl; wherein m is a number selectedfrom zero through three; wherein n is a number selected from zerothrough three; wherein R⁷ is selected from cyclohexylmethyl and benzyl,either one of which may be substituted with one or more groups selectedfrom alkyl, hydroxy and alkoxy; wherein R⁸ is selected from hydrido,alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkenyl andhaloalkenyl; and wherein each of R¹² and R¹³ is independently selectedfrom hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, halophenyl,phenylalkyl, halophenylalkyl, naphthyl, halonaphthyl, naphthylalkyl andhalonaphthylalkyl; or a pharmaceutically-acceptable salt thereof. 17.The method of claim 16 wherein each of R¹ and R¹¹ is independentlyselected from hydrido, methyl, ethyl, n-propyl and isopropyl; wherein pis a number selected from zero through three, inclusive; wherein r is anumber selected from zero, one and two; wherein R² is selected fromhydrido, methyl, ethyl and n-propyl; wherein R³ is selected fromhydrido, cyclohexylmethyl, benzyl, phenylethyl, fluorobenzyl,fluorophenylethyl, chlorobenzyl, chlorophenylethyl, naphthylmethyl,naphthylethyl, fluoronaphthylmethyl and chloronaphthylmethyl; whereineach of R⁴ and R⁶ is independently selected from hydrido and methyl;wherein R⁵ is selected from

wherein V is selected from hydrido, alkyl, cycloalkyl, aryl and aralkyl;wherein m is a number selected from one through three; wherein R⁷ iscyclohexylmethyl; wherein R⁸ is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl,cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, allyland vinyl; and wherein each of R¹² and R¹³ is independently selectedfrom hydrido, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl,propylcarbonyl, ethylcarbonyl, methylcarbonyl, phenyl, benzyl,phenylethyl, monochlorophenyl, dichlorophenyl, monofluorophenyl,difluorophenyl, monochlorophenylmethyl, monochlorophenylethyl,dichlorophenylmethyl, dichlorophenylethyl, naphthyl, monofluoronaphthyl,monochloronaphthyl, naphthylmethyl, naphthylethyl, fluoronapthylmethyland chloronaphthylethyl; or a pharmaceutically-acceptable salt thereof.18. The method of claim 17 wherein each of R¹ and R¹¹ is independentlyhydrido or methyl; wherein p is a number selected from zero throughthree, inclusive; wherein r is zero or two; wherein R² is selected fromhydrido, methyl, ethyl and n-propyl; wherein R³ is selected fromhydrido, cyclohexylmethyl, benzyl, phenylethyl, phenylpropyl,fluorobenzyl, fluorophenylethyl, chlorobenzyl, chlorophenylethyl,naphthylmethyl, naphthylethyl, fluoronaphthylmethyl andchloronaphthylmethyl; wherein each of R⁴ and R⁶ is hydrido; wherein R⁵is selected from

wherein V is selected from hydrido and methyl; wherein m is one or two;wherein R⁷ is cyclohexylmethyl; wherein R⁸ is selected from ethyl,n-propyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopropylmethyl,allyl and vinyl; wherein each of R¹² and R¹³ is independently selectedfrom hydrido, methyl, ethyl, n-propyl, isopropyl, cyclopropylmethyl,phenyl, benzyl, monochlorophenyl and dichlorophenyl; or apharmaceutically-acceptable salt thereof.
 19. The method of claim 18wherein said compound is of Formula II

wherein r is zero or two; wherein q is two or three; wherein R² isselected from hydrido, methyl, ethyl and phenyl; wherein R³ is selectedfrom hydrido, cyclohexylmethyl, benzyl, fluorobenzyl, chlorobenzyl,fluoronaphthylmethyl and chloronaphthylmethyl; wherein each of R⁴ and R⁶is hydrido; wherein R⁵ is selected from

wherein V is selected from hydrido and methyl; wherein m is one or two;wherein R⁷ is cyclohexylmethyl; wherein R⁸ is selected from n-propyl,isobutyl, cyclopropyl, cyclopropylmethyl, allyl and vinyl; wherein R¹²and R¹³ is independently selected from methyl, ethyl and isopropyl; or apharmaceutically-acceptable salt thereof.
 20. The method of claim 18wherein said compound is selected from compounds, their tautomers andpharmaceutically-acceptable salts thereof, of the group consisting of:


21. The method of claim 20 wherein said compound isN-[1R*-[[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]carbonyl]-3-butynyl]-αR*-[[[2-(dimethylamino)ethyl]sulfonyl]methyl]benzenepropanamide.22. The method of claim 15 for treating hypertension.
 23. The method ofclaim 15 for treating glaucoma.